PEGylation has been widely recognized as one of the most important approaches for drug modification. Wherein, functional polyethylene glycols (PEGs), owing to their reactive groups, are capable of modifying therapeutic drugs and other bio-related substances by covalently binding to target molecules, generally small molecule organic drugs or biomolecules, including proteins, peptides, saccharides, lipids, oligonucleotides, affinity ligands, cofactors, liposomes, biomaterials and the like. The pegylated drugs can be endowed with many beneficial properties in the aspect of hydrophilicity, flexibility, antithrombogenicity, etc. Meanwhile, due to the steric repulsion effect, pharmaceutical drugs modified with polyethylene glycol can avoid the filtration through glomeruli in the kidney and the bio-reactions such as immunoreactions, so that longer half-life in blood is achieved compared with the unmodified form. For example, it has been reported that paclitaxel, a water-insoluble drug, when coupled to polyethylene glycol, becomes water-soluble (Greenwald et al., J. Org. Chem. 1995, 331-336).
In 1995, Monfardini and coworkers synthesized a branched polyethylene glycol derivative with two arms, also denoted as “V-shaped” PEG, wherein, two linear monomethoxy polyethylene glycol chains were directly linked to the two amino groups of lysine followed by activation of the α-carboxyl group of lysine into a succinimidyl ester group, and thereafter investigated modification of proteins with the branched polyethylene glycol (Bioconjugate Chem. 1995, 6, 62-69). Since then, it has gained popularity as a tool to produce a monofunctional branched polyethylene glycol and drug derivatives thereof, and has already been applied in three commercially available pharmaceutical products. Compared with a linear polyethylene glycol having the same molecular weight, a branched polyethylene glycol, in virtue of its particular molecular structure, can provide an “umbrella-like” protective coverage around protein surface which increases steric hindrance around the drug molecule, inhibit the attack from other macromolecules in vivo more effectively so as to decrease inactivation and enzymolysis in body and therefore extend the circulation time of pegylated drugs.
In addition to linear monofunctional and linear bifunctional polyethylene glycols, multiarm polyethylene glycols such as three-arm, four-arm, six-arm and eight-arm polyethylene glycols, thanks to their advantages in structure and drug loading, have also occupied a place in the commercial market. Especially for small molecule drugs, the drawbacks including low solubility and high toxicity greatly limit their clinical applications. When using traditional linear polyethylene glycol for modification, no matter monofunctional or bifunctional polyethylene glycols, improved solubility and reduced toxic side effect can be achieved, but because drug molecules are probably embedded by the PEG chain, the drug activity may be greatly reduced. Compared with linear polyethylene glycol derivatives, multiarm branched polyethylene glycol derivatives can simultaneously achieve increasement in solubility, decreasement in toxic side effect and high maintenance of drug activity. Additionally, the multiarm structure also leads to reduced viscosity and facilitates better pharmacokinetics. So far, there are two cases of four-arm PEG-modified small molecule drugs into the clinical stage II or III.
Compared with four-arm polyethylene glycol derivatives, eight-arm polyethylene glycol derivatives provide higher drug loading, better solubility and higher drug activity. Regarding eight-arm polyethylene glycol derivatives, two kinds of octavalent central groups including —O[CH2CH(O—)CH2O]6— of a tripentaerythritol type and —O[CH2CH(O—)CH2O]6— of a hexaglycerol type have been disclosed. To the best of our knowledge, they have not yet entered preclinical study or clinical trials
Since the intramolecular ether bond inside the PEG structure (CH2CH—O—CH2CH2) is relatively stable, the eight-arm polyethylene glycol molecules of the above two kinds are considered to be undegradable. Moreover, the asymmetry of the octavalent central groups may cause a difference in the reactivity of the eight active sites when initiating polymerization of ethylene oxide, and thus result in different PEG chain lengths and undesired homogeneity of the molecular weight.